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000280468 1001_ $$0P:(DE-Juel1)166112$$aLi, Jinyu$$b0
000280468 245__ $$aInsight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)
000280468 260__ $$aLawrence, Kan.$$bPLoS$$c2015
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000280468 520__ $$aSirtuin 2 (SIRT2) is a NAD+-dependent deacetylase that has been associated with neurodegeneration and cancer. SIRT2 is composed of a central catalytic domain, the structure of which has been solved, and N- and C-terminal extensions that are thought to control SIRT2 function. However structural information of these N- and C-terminal regions is missing. Here, we provide the first full-length molecular models of SIRT2 in the absence and presence of NAD+. We also predict the structural alterations associated with phosphorylation of SIRT2 at S331, a modification that inhibits catalytic activity. Bioinformatics tools and molecular dynamics simulations, complemented by in vitro deacetylation assays, provide a consistent picture based on which the C-terminal region of SIRT2 is suggested to function as an autoinhibitory region. This has the capacity to partially occlude the NAD+ binding pocket or stabilize the NAD+ in a non-productive state. Furthermore, our simulations suggest that the phosphorylation at S331 causes large conformational changes in the C-terminal region that enhance the autoinhibitory activity, consistent with our previous findings that phosphorylation of S331 by cyclin-dependent kinases inhibits SIRT2 catalytic activity. The molecular insight into the role of the C-terminal region in controlling SIRT2 function described in this study may be useful for future design of selective inhibitors targeting SIRT2 for therapeutic applications.
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000280468 7001_ $$0P:(DE-HGF)0$$aFlick, Franziska$$b1
000280468 7001_ $$0P:(DE-HGF)0$$aVerheugd, Patricia$$b2
000280468 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b3$$ufzj
000280468 7001_ $$0P:(DE-HGF)0$$aLüscher, Bernhard$$b4
000280468 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b5$$eCorresponding author
000280468 773__ $$0PERI:(DE-600)2267670-3$$a10.1371/journal.pone.0139095$$gVol. 10, no. 9, p. e0139095 -$$n9$$pe0139095 -$$tPLoS one$$v10$$x1932-6203$$y2015
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